Inhibition Of Er Stress-Related Ire1 Alpha/Creb/Nlrp1 Pathway Promotes The Apoptosis Of Human Chronic Myelogenous Leukemia Cell

Endoplasmic reticulum (ER) stress is induced in chronic myelogenous leukemia (CML) cells. As an important sensor of ER stress, inositol-requiring protein-1 alpha (IRE1 alpha) promotes the survival of acute myeloid leukemia. NLRP1 inflammasome activation promotes metastatic melanoma growth and that IRE1 alpha can increase NLRP1 inflammasome gene expression. This study aimed to investigate the role and molecular mechanism of IRE1 alpha in CML cell growth. We found that overexpression of IRE1 alpha or NLRP1 significantly promoted the proliferation and decreased the apoptosis of CML cells, whereas downregulation of these two genes showed the opposite effects. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, reduced the expression of IRE1 alpha and NLRP1. IRE1 alpha elevated NLRP1 expression via cAMP responsive element binding protein (CREB) phosphorylation. NLRP1 inflammasome was activated in CML cells and its activation partly reversed ER stress inhibitor-induced cell apoptosis. Furthermore, inhibition of IRE1 alpha/NLRP1 pathway sensitized CML cells to imatinib-mediated apoptosis. Additionally, IRE1 alpha expression was elevated and NLRP1 inflammasome was activated in primary cells from CML patients. Downregulation of IRE1 alpha or NLRP1 suppressed the proliferation and elevated the apoptosis of primary CML cells. Collectively, this study demonstrated that the IRE1 alpha/CREB/NLRP1 pathway contributes to the progression of CML and the development of imatinib resistance. Hence, targeting ER stress-related IRE1 alpha expression or NLRP1 inflammasome activation may block CML development.